Stabilized choline salicylate compounds

ABSTRACT

Choline salicylate sulfite and choline salicylate alkali metal sulfite-containing compounds of the formula, ##STR1## wherein Me represents the sodium, potassium or lithium ion and R represents the sulfite, bisulfite metabisulfite, dithionate, hydrosulfite and hyposulfite groups are described. Said compounds are stable and inhibit the formation of color in pharmaceutical preparations containing the same. The method for the preparation of choline salicylate sulfite and choline salicylate alkali metal sulfite-containing compounds, and pharmaceutical dosage forms containing the same are disclosed together with a method for their use to inhibit color formation.

This is a division, of application Ser. No 501,004 filed Sept. 3, 1974,now U.S. Pat. No. 3,947,491; which, in turn, is a division of Ser. No.237,927, filed Mar. 24, 1972, now U.S. Pat. No. 3,855,282.

This invention relates to stabilized compounds of choline salicylate,the method for producing the same and pharmaceutical compositionscontaining the aforesaid stabilized compounds. In particular it relatesto a molecular coordination compound formed between choline salicylateand an alkali metal sulfite-containing compound and/or sulfur dioxide,the method for the preparation of aforesaid compounds and pharmaceuticalcompositions containing the same as well as the methods for the use ofsaid pharmaceutical compositions.

Choline salicylate is described in U.S. Pat. No. 3,069,321, (Dec. 18,1962). Choline salicylate has unique advantages over other salicylatecompounds and it has been introduced into therapy as an activeingredient of a large number of pharmaceutical dosage forms includingsolutions, syrups, ointments, gels, lozenges, tablets, capsules andsuppositories.

An inherent disadvantage to the use of chloine salicylate in bothpharmaceutical manufacture and therapy is the appearance of a color informulations containing choline salicylate, whether prepared in aqueousor nonaqueous solvents; liquid or solid dosage forms. This colorformation necessitates manufacture of multiple batches to avoid storingthe compound for extended periods, thereby increasing costs throughmultiple handling operations. The appearance of a color in a finishedpharmaceutical dosage-form causes confusion and concern to the patient,who is unaware of the nature of this change, thereby possiblyinterrupting therapy.

Although the exact cause of color formation in choline salicylateformulations is not known and various theories for its origin have beenproposed, it is generally accepted than an electron shift in molecularconfiguration takes place to produce a chromophore. It is an object ofthe present invention to prevent, as well as to substantially reduce,the formation of color in choline salicylate preparations, whether inliquid or solid dosage form, or in bulk preparations intended to be usedin further manufacture.

It was found that the suppression or avoidance of the aforesaid colorformation in compositions containing choline salicylate may be achievedthrough the formation of a molecular coordinate compound between cholinesalicylate and an alkali metal sulfite-containing compound as forexample, sodium bisulfite (NaHSO₃), sodium metabisulfite (Na₂ S₂ O₅),sodium hydrosulfite (Na₂ S₂ O₄), sodium dithionate (Na₂ S₂ O₆ 2H₂ O),sodium hyposulfite (Na₂ S₂ O₂) and sodium sulfite (Na₂ SO₃) or thecorresponding lithium and potassium salts. Sulfur dioxide also forms amolecular compound with choline salicylate and therefore the point ofcoordination may be said to be through the sulfite group. The newmolecular coordination compounds may be considered to inhibit theelectron shift necessary to form a chromophore and thereby inhibit colorformation. According to one aspect of the invention therefore, there isprovided as a new composition of matter, the compound formed betweencholine salicylate and an alkali metal sulfite-containing compound andsulfur dioxide as well as compositions comprising the same, saidcomposition being substantially free from color formation.

The formation of the new molecular coordination compound between analkali metal sulfite-containing compound and choline salicylate isestablished through the change in specific electrical conductance of asolution containing said compound. When two or more substances areintroduced into the same solvent, the specific electrical conductivityof the mixture will be generally expressed as the arithmetic sum of thenumber of ions present in solution. However, if molecular complexingoccurs among the molecules in solution, then this is reflected in thenature of the change observed in specific electrical conductivity forthe mixture.

If the specific electrical conduction of a mixture of substances insolution is greater than the additive sum of the separate conductivityvalues of the components, then this establishes that a new molecularchange has taken place to increase the electrical conductivity of thenew molecule in solution. The presence of the newly formed compound isdemonstrated through the increase in specific electrical conductivitysince it possesses a property that is different from the mixture of theseparate component substances.

If the specific electrical conductivity of the mixture is less than thearithmetic sum of the individual conductivity values determined for thecomponent in solution, then a new molecular compound is formed that hasa reduced electrical conductivity or a decreased ionizing potential insolution. This may occur through an internal electron sharing resultingin a depressed level of ionization for the new compound. Such complexinghas been observed after the formation of chelate compounds.

When no new chemical bond results so that there is no modification inthe electrical conductivity of the mixture of substances in solution,then the specific electrical conductivity for the mixture remainssubstantially the additive sum of the values for the separate moieties.

The method used in determining the specific electrical conductance of asolution is to measure the degree of resistance encountered to the flowof a standard electrical current through an accurately measured volumeof solution. The resistance to the flow of electrical current (ohms) isdetermined for a volume of the conductor solution 1 cm long at eachedge. The specific conductance of the solution is thereby computed asthe reciprocal of the specific resistance and is expressed in unitstermed mhos, the reciprocal of ohms.

When the specific electrical conductivity of choline salicylate inaqueous solution was determined, it was found than an 0.5 molar solutionof choline salicylate has an electrical resistance of 2.3 ohms and aspecific conductance of 0.035 mhos/cm. The electrical resistancedetermined for an 0.5 molar solution of sodium bisulfite was 0.8 ohmsand the specific electrical conductance was computed to be 0.10 mhos/cm.However, when an 0.5 molar solution of choline salicylate was reactedwith an 0.5 molar solution of sodium bisulfite, the specifice electricalconductivity determined it was found to be 0.007 mhos/cm. This value ismarkedly less than the expected arithmetic sum of the separateelectrical conductivity values for the mixture of components. Thecalculated arithmethic sum of the specific electrical conductance of thecomponents in the aforesaid mixture is 0.135 mhos/cm. This demonstratesthat a new molecule formed between choline salicylate and sodiumbisulfite which possessed a decreased ionizing potential different fromthat expected for a mixture of choline salicylate and sodium bisulfite.

In a similar manner it was found that an increase in the electricalresistance occured with a consequent decrease in specific electricalconductivity when other alkali metal sulfite compounds were caused toreact with choline salicylate. Thus, when such compounds as sodiumdithionate (Na₂ S₂ O₆), sodium methabisulfite (Na₂ S₂ O₅), sodiumhydrosulfite (Na₂ S₂ O₄), sodium sulfite (Na₂ SO₃), and sodiumhyposulfite (Na₂ S₂ O₂), or the respective corresponding lithium andpotassium sulfite salts are reacted with choline salicylate, a newcompoisition of matter formed having different properties than themixture of its components. It was further found that new compoundformation apparently takes place through the sulfite radical. Gaseoussulfur dioxide also reacted with choline salicylate to produce a newcompound, choline salicylate sulfite. The aforesaid new compounds do notexhibit color formation on storage and when added to phenolic colorforming compounds block or suppress the formation of a color.

The new compounds are preferably formed concurrently with the synthesisof choline salicylate, although the new compounds will form when theappropriate sulfite-containing reagent is reacted with formed cholinesalicylate. The new compound formed between choline salicylate and therespective alkali metal sulfite-containing salts or sulfur dioxide maybe in the form of the solid choline salicylate-sulfite compound orpresent in solution. When the new compositions are formed at the time ofthe synthesis of choline salicylate, then the appropriatesulfite-containing compound, described above, is dissolved in theaqueous medium or polar solvent used as the medium for the reaction.When the new compound is desired to be formed, after the synthesis ofcholine salicylate, then the appropriate sulfite-containing compounddescribed above is added to the formed choline salicylate either insolution or in the dry form. However, minimal quantities of water arepreferred when forming the new choline salicylate alkali metalsulfite-containing compounds. The commercial grade of the respectivesulfite-containing compounds have water of crystallization and this issufficient to cause the reaction to proceed when the solid reagents aremixed. Thus if it is desired to use the solid forms of both thesulfite-containing compound and the choline salicylate, the newcompounds will form nevertheless. This is of special importance to thepreparation of solid pharmaceutical dosage forms containing cholinesalicylate.

In one preferred form of carrying out the invention a solution ofcholine carbonate is mixed with salicylic acid dissolved in watercontaining the appropriate quantity of sodium metabisulfite. Care isexercised during the addition of the reagents that the pH of the mediumdoes not exceed the limits of pH 5 to pH 7. The reaction proceedssmoothly and gaseous carbon dioxide is liberated to result in asubstantially pure solution of choline salicylate sodium metabisulfite.This solution may be used in further manufacture of pharmaceuticaldosage forms or used directly. In place of the sodium metabisulfitedescribed above, one may use another alkali metal metabisulfite, analkali metal dithionate, an alkali metal bisulfite, an alkali metalhydrosulfite, an alkali metal sulfite and an alkali metal hyposulfite.Gaseous sulfur dioxide may also be used to introduce the sulfite group.The choline salicylate sodium metabisulfite may, if desired, berecovered in solid form although this is not necessary for furtherpharmaceutical manufacture and the solution of the formed cholinesalicylate sodium metabisulfite may be used as such.

In practice, it will be found that the new compounds, choline salicylatealkali metal bisulfite, choline salicylate alkali metal metabisulfite,choline salicylate alkali metal sulfite, choline salicylate alkali metaldithionate, choline salicylate alkali metal hydrosulfite, cholinesalicylate alkali metal hyposulfite and choline salicylate sulfitewhether in solid form or in solution, will be substantially free ofcolor even after prolonged periods of storage. This may be readilydemonstrated by comparing the color formed after heating for 24 hours at90° C to 95° C in an aqueous solution of choline salicylate with thatpresent in a similar treated solution containing an equivalentconcentration of the new compounds. When the aforesaid respectivesolutions are heated for 24 hours at a temperature of from 90° C to 95°C, a pink color is found to develop in the aqueous solution of cholinesalicylate whereas the solutions prepared with the new compounds arevirtually colorless.

According to another aspect of the invention there is provided a processfor the production of solutions of choline salicylate normally having atendency to form a color which comprises the reaction of cholinesalicylateforming regeants, preferably choline carbonate or cholinebicarbonate and salicylic acid, mixed in the presence of an effectiveamount of an alkali metal sulfite-containing compound, as for example,an alkali metal bisulfite, alkali metal metabisulfite, alkali metalhydrosulfite, alkali metal hyposulfite, alkali metal dithionate, alkalimetal sulfite and/or sulfur dioxide whereby the choline salicylate isformed in the presence of the effective amount of saidsulfite-containing compound. The aforesaid reaction may be carried outin the presence of water, ethanol, glycerin, propylene glycol,polyoxyethylene glycol or mixtures of the same. Gentle warming may beutilized to remove any of the volatile by-products and the resultingsolution of choline salicylate is sufficiently pure for use as such oras an ingredient in further pharmaceutical manufacture. In this manner,appropriate solutions of choline salicylate ranging in concentrations upto 90 percent by weight of choline salicylate, may be obtained insubstantially pure form that do not show evidence of color formationeven upon prolonged storage. The effective concentration of the alkalimetal sulfite-containing compound described above is at least 0.01percent by weight and not more than 5.0 percent by weight, with apreferred range being from 0.05 percent to 2.5 percent by weight basedupon the weight of choline salicylate active ingredient.

It may be found desirable to introduce the sulfite-containing compoundin the form of gaseous sulfur dioxide in which event, the effectivequantity of sulfur dioxide to be used is the same as described above forthe effective amounts of the alkali metal sulfite-containing compounds.An advantage of gaeous sulfur dioxide is the avoidance of theintroduction of alkali metal ions which may not be desirable inpharmaceutical preparations intended to treat certain pathologic states.

Still another method for the production of solutions of cholinesalicylate substantially free of color is to add an effective quantityof the respective new choline salicylate sulfite-containing compound, asfor example, choline salicylate sulfite, choline salicylate alkali metalbisulfite, choline salicylate alkali metal metabisulfite, cholinesalicylate alkali metal dithionate, choline salicylate alkali metalhydrosulfite, choline salicylate alkali metal hyposulfite and cholinesalicylate alkali metal sulfite to a solution of choline salicylate.When it is desired to utilize the aforesaid choline salicylatesulfitecontaining compounds to stabilize a preparation containingcholine salicylate, whether in the liquid or solid form, then a quantityof the aforesaid choline salicylate sulfite-containing compound of notless than 0.01 percent by weight is used and not more than 5.0 percentby weight, with a preferred range from 0.05 percent to 2.5 percent byweight, based upon the volume or weight of the active ingredient beingstabilized. In achieving this stabilizing effect, then an appropriatequantity of the aforesaid stabilizing compound is added to a solution ofcholine salicylate in the appropriate quantity after the synthesis ofcholine salicylate or it may be incorporated in appropriate quantitiesto the finished pharmaceutical formulation containing cholinesalicylate. In either event, the resultant product will be substantiallyfree from color formation. In this manner, pharmaceutical preparationssuch as solutions, gels, ointments, tablets, lozenges, capsules andsuppositories containing choline salicylate may be prepared to besubstantially color-free for prolonged periods of time.

The choline salicylate sulfite-containing compounds have the furtheradvantage of suppressing color formation in pharmaceutical preparationscontaining salicylate compounds such as aspirin, salicylic acid,metallic salts of salicylic acid, para-aminosalicylic acid, metallicsalts or para-amino salicylic acid, esters of salicylic acid such asmethyl salicylate and menthyl salicylate and N-methylglucaminesalicylate. Such pharmaceutical preaparations may be rendered free ofcolor formation by the addition of the aforesaid choline salicylatesulfite-containing compounds to said salicylate-containingpharmaceutical preparations and the amount of choline salicylatesulfite-containing compound to be added to suppress color formation isnot less than 0.1 percent by weight and not more than 5.0 percent byweight of the choline salicylate sulfite-containing compound, based uponthe amount of salicylate active ingredient in the preparation to bestabilized.

In practice, the stabilizing choline salicylate sulfite-containingcompound is mixed either with the salicylate active ingredient or it maybe incorporated into the formulation prior to the finishing step. Thesequence for the addition of the preservative compound will depend uponthe nature of the pharmaceutical preparation being stabilized. Whenimmiscible substances are utilized, as for example, oil, water systems,it is the water phase which should receive the preservative compound,even though the active salicylate compound may be dissolved in the oilphase.

Thus, should it be desired to stabilize a tablet containing a salicylatecompound, as for example, N-methylglucamine salicylate, aspirin, ormetallic salt of salicylic acid, then not less than 0.1 percent byweight and not more than 0.5 percent by weight of the selected cholinesalicylate sulfitecontaining compound is mixed with the salicylateactive ingredient. The mixture is then added to appropriate diluents,binding and granulating agents and the whole granulated to prepare agranulation tableting mix. The mixture is then compressed into unittablets of suitable size and shape containing the desired quantity ofactive ingredient. The finished tablets will remain substantially freeof color for prolonged periods of time.

An alternate procedure for stablizing the aforesaid salicylatecontainingtablet is to add the selected choline salicylate sulfite-containingcompound to the mixture of the selected salicylate compound, diluent,binders and granulating agents prior to the granulation step. In thisevent, the stabilizing compound is thoroughly mixed with the granulationmixture to assure a uniform dispersion.

In a similar manner, the choline salicylate sulfite-containing compoundmay be mixed with the appropriate salicylate active ingredient prior toits incorporation in an ointment, gel or solution. When it is intendedto preserve a salicylate solution against a color formation, then thepreservative compound is preferably added prior to the introduction of,or concommitantly with, the salicylate active ingredient, although abeneficial preservative effect will be observed if the stabilizingcompound is added prior to the finishing step.

The following examples illustrate the present invention but it is notintended to be limited thereby.

EXAMPLE 1

To an 0.5 molar aqueous solution of choline carbonate is added 52.5grams of sodium bisulfite (anhydrous) and 69.0 grams of salicylic acid.Each of the solid reagents are added alternately in samll increments andwith constant stirring. The pH of the solution is determined immediatelyafter the addition of each increment to avoid a drop in the pH of thesolution below pH 4. When all of the solid reagents have been added andthe ebullition of carbon dioxide has stopped, the solution is gentlywarmed to 35° C to remove an residual dissolved carbon dioxide. Thesolution of choline salicylate sodium bisulfite, thus formed, isessentially color-free and is in a sufficient state of purity to be usedas such or for further pharmaceutical manufacture. The compound, cholinesalicylate sodium bisulfite analyzes in good agreement with itstheoretical values for salicylate content. Calculated: 57 percent, byweight, salicylate moiety based upon the weight of choline salicylate:Found: 56.9 percent of salicylate moiety.

On heating the solution of the formed choline salicylate sodiumbisulfite for 24 hours at a temperature of from 90° C to 95° C, there isvirtually no change from the orginal color. The pH of the solution ofcholine salicylate sodium bisulfite is between pH 6 and pH 6.8.

The electrical conductivity of an 0.5 molar solution of cholinesalicylate sodium bisulfite determined at 25° C is 6.654 × 10⁻ ³. Thespecific electrical conductivity of an 0.5 molar aqueous solution ofcholine salicylate is 3.448 × 10⁻ ². The specific electricalconductivity of an 0.5 molar solution of sodium bisulfite is 9.9125 ×10⁻ ². The calculated specific electrical conductivity for a mixturecomprising an 0.5 molar solution of choline salicylate and an 0.5 molarsodium bisulfite solution is 13.3605 × 10⁻ ², based upon theirarithmetic sum of the values. The difference in electrical conductivityexhibited by choline salicylate sodium bisulfite and that of itscomponent moieties establish the formation of a new compound.

EXAMPLE 2

To 500 cc. of propylene glycol is added 82.6 grams of cholinebicarbonate, and the mixture is stirred until complete solution isachieved. 95.06 grams of sodium metabisulfite and 69.0 grams ofsalicylic acid are added in small increments while controlling the pH tobe between pH 4.5 and pH 7. The mixture is stirred until the ebullitionof carbon dioxide has stopped. Gentle warming may be used to achievesolution and to facilitate the removal of carbon dioxide. The solutioncontains the formed choline salicylate sodium metabisulfite.

A representative sample of the formed choline salicylate sodiummetabisulfite solution is diluted with sufficient distilled water toprovide a concentration of 0.1 molar choline salicylate sodiummetabisulfite and the specific electrical conductivity was determined tobe 1.064 × 10⁻ ². The specific electrical conductivity for 0.1 molarsolution of choline salicylate is 4.19 × 10⁻ ³ and the specificelectrical conductivity for 0.1 molar solution of sodium metabisulfiteis 1.46 × 10⁻ ². The decrease in specific electrical conductivity forthe compound, choline salicylate sodium metabisulfite when compared withthe arithmetic sum of the conductivities for the mixture of the separatemoieties establishes the formation of a new compound.

EXAMPLE 3

To a suitable vessel containing 100 cc. of distilled water is added 14grams of choline chloride and 17.4 grams of sodium hydrosulfite. Themixture is stirred to achieve solution and 16 grams of sodiumsalicylate, dissolved in 100 cc. of water are added. The solvent isremoved under vacuum to obtain a slurry which is dissolved in absolutemethanol and filtered. Anhydrous ether is added to the point ofcloudiness and the whole set aside in an ice chest to crystallize. Thecrystalline material is collected, dried under vacuum to result in thehygroscopic crystalline salt, choline salicylate sodium hydrosulfite.The specific electrical conductivity determined for an 0.1 molarsolution of choline salicylate sodium hydrosulfite is 8.8 × 10⁻ ⁴. Thisvalue is less than the sum of the individual specific electricalconductivities for the separate moieties.

EXAMPLE 4

In a suitable vessel containing 100 ml. of distilled water is added 0.1mol of choline citrate and 0.1 mol of lithium salicylate. The mixture isstirred until complete solution is achieved. The solvent is removed byvacuum distillation and the residue dissolved in anhydrous amyl alcoholand filtered. The solution is set aside to crystallize in an ice chestafter the addition of sufficient acetone to cause clouding. Thecrystallized lithium citrate is removed by filtration and the filtrateconcentrated under vacuum. To the residue is added 250 cc. of 0.1 molaraqueous solution of sodium hyposulfite and the mixture is filtered andthe solvent removed once again under vacuum to yield choline salicylatesodium hyposulfite.

The specific electrical conductivity determined for an 0.5 molarsolution of choline salicylate sodium hyposulfite is 6.31 × 10⁻ ³, whichis less than the calculated sum of the specific electricalconductivities determined for an equimolar concentration of the separatemoieties.

EXAMPLE 5

To an aqueous solution consisting of 5 grams of choline salicylate,dissolved in 100 ml. of distilled water is added 72.6 grams of sodiumdithionate. The mixture is stirred and filtered. The filtrate containsthe solution of choline salicylate sodium dithionate which may be usedin further pharmaceutical manufacture or dispensed as such. Thearithmetic sum of the specific electrical conductivity for equimolarconcentrations of sodium dithionate and choline salicylate is 9.82 × 10⁻². The specific electrical conductivity of an 0.25 molar solution ofcholine salicylate sodium dithionate is 5.36 × 10⁻ ², which is less thanthe calculated sum of the separate values.

EXAMPLE 6

To an aqueous solution containing 28.5 grams of choline carbonate isadded 13.8 grams of salicylic acid and 12.6 grams of sodium sulfite. Themixture is stirred until complete solution is achieved and theebullition of gases cease. The solution of choline salicylate sodiumsulfite thus formed is sufficiently pure to be used for furtherpharmaceutical manufacture. The compound choline salicylate sodiumsulfite may be obtained by removing the solvent under high vacuum withthe aid of gentle warming. The compound is a colorless crystal, that ishighly hygroscopic, rapidly absorbing water on exposure to theatmosphere. An 0.1 molar solution of choline salicylate sodium sulfitehas a specific electrical conductivity of 8.16 × 10⁻ ³.

EXAMPLE 7

In a three-neck round-bottom flask fitted with a stirring rod, a gasinlet tube and an exhaust vent fitted with a trap, is placed 100 ml. of0.1 molar aqueous solution of choline salicylate. The stirring isstarted and the solution cooled to about 0° C. Gaseous sulfur dioxide isthen passed through the solution until the rise in the net weight of thesolution is 8 grams. Care is taken that the temperature of the solutiondoes not rise above 5° C. When the required quantity of sulfur dioxidehas been added, the stirring is continued while the solution warms toroom temperature. An equal volume of distilled water is added and theresulting solution containing the formed choline salicylate sulfurdioxide is in sufficiently pure form for use as such or for furtherpharmaceutical manufacture. The 0.05 molar solution of cholinesalicylate sulfite has a specific electrical conductivity of 9.87 × 10⁻⁴.

EXAMPLE 8

In place of sodium bisulfite used as described in Example 1 above;sodium metabisulfite, used as described in Example 2 above; sodiumhydrosulfite used as described in Example 3 above; sodium hyposulfiteused as described in Example 4 above; sodium dithionate used asdescribed in Example 5 above, and sodium sulfite used as described inExample 6 above, there may be substituted in equimolar proportions acompound selected from the group consisting of sodium sulfite, sodiumbisulfite, sodium metabisulfite, sodium dithionate, sodium hydrosulfite,sodium hyposulfite, lithium sulfite, lithium bisulfite, lithiummetabisulfite, lithium dithionate, lithium hydrosulfite, lithiumhyposulfite, potassium sulfite, potassium bisulfite, potassiummetabisulfite, potassium dithionate, potassium hydrosulfite andpotassium hyposulfite. The remainder of the steps being the same therespective choline salicylate alkali metal sulfite-containing compoundis formed. An 0.05 molar aqueous solution of the aforesaid formedcholine salicylate alkali metal sulfite-containing compound has thefollowing specific electrical conductivity.

    __________________________________________________________________________                                 Specific                                                                Electrical                                                                          Electrical                                                              Resistance                                                                          Conductivity                                     Compound               (ohms)                                                                              (× 10.sup..sup.-3 mhos)                    __________________________________________________________________________    Choline Salicylate Sodium Sulfite                                                                    41.1  1.93                                             Choline Salicylate Sodium Bisulfite                                                                  30.4  2.61                                             Choline Salicylate Sodium Metabisulfite                                                              18.8  4.21                                             Choline Salicylate Sodium Dithionate                                                                 16.8  4.71                                             Choline Salicylate Sodium Hydrosulfite                                                               34.3  2.31                                             Choline Salicylate Sodium Hyposulfite                                                                27.3  2.91                                             Choline Salicylate Potassium Sulfite                                                                 37.2  2.13                                             Choline Salicylate Potassium Bisulfite                                                               26.3  3.01                                             Choline Salicylate Potassium Metabisulfite                                                           15.5  5.13                                             Choline Salicylate Potassium Dithionate                                                              17.3  4.58                                             Choline Salicylate Potassium Hydrosulfite                                                            22.0  3.61                                             Choline Salicylate Potassium Hyposulfite                                                             25.4  3.12                                             Choline Salicylate Lithium Sulfite                                                                   37.2  2.13                                             Choline Salicylate Lithium Bisulfite                                                                 28.2  2.81                                             Choline Salicylate Lithium Metabisulfite                                                             16.2  4.89                                             Choline Salicylate Lithium Dithionate                                                                15.6  5.07                                             Choline Salicylate Lithium Hydrosulfite                                                              27.3  2.91                                             Choline Salicylate Lithium Hyposulfite                                                               23.2  3.42                                             __________________________________________________________________________

The specific electrical conductivity for an 0.05 molar solution of theseparate reagents is:

    ______________________________________                                                       Electrical                                                                              Specific Electrical                                                 Resistance                                                                              Conductance                                          Reagent        (ohms)    (×  10.sup..sup.-3 mhos)                       ______________________________________                                        Sodium sulfite 51.4      1.543                                                Sodium bisulfite                                                                             34.3      2.31                                                 Sodium metabisulfite                                                                          18.17    4.36                                                 Sodium dithionate                                                                            17.1      4.637                                                Sodium hydrosulfite                                                                          39.9      1.987                                                Sodium hyposulfite                                                                           29.9      2.652                                                Lithium sulfite                                                                              49.6      1.764                                                Lithium bisulfite                                                                            37.1      2.137                                                Lithium metabisulfite                                                                        17.9      4.430                                                Lithium dithionate                                                                           17.0      4.665                                                Lithium hydrosulfite                                                                         37.7      2.103                                                Lithium hyposulfite                                                                          28.9      2.744                                                Potassium sulfite                                                                            47.2      1.680                                                Potassium bisulfite                                                                          32.1      2.470                                                Potassium metabisulfite                                                                      16.9      4.692                                                Potassium dithionate                                                                         16.3      4.800                                                Potassium hydrosulfite                                                                       26.1      3.038                                                Potassium hyposulfite                                                                        26.7      2.970                                                Choline salicylate                                                                           78.4      1.01                                                 ______________________________________                                    

EXAMPLE 9

To 100 ml. of a 50 percent solution of choline carbonate, dissolved indistilled water, is added 0.25 grams of sodium bisulfite. The mixture isstirred until solution is achieved. To this solution is then added 27.6grams of salicylic acid in small increments while stirring. Carbondioxide is liberated and when the ebulliton of gas ceases, the aqueoussolution of choline salicylate thus formed contains a stabilizingquantity of choline salicylate sodium bisulfite and said solution may bedispensed directly in unit dosage form to achieve its intendedtherapeutic effect.

Should a liquid pharmaceutical preparation be desired, other than asolution, as for example, a syrup, then the appropriate quantity ofsugar is added after the ebullition of carbon dioxide ceases. When anelixir is intended, then the proper quantity of ethanol is added forpart of the water used to form the solution of choline carbonate.Gylcerin, propylene glycol and polyoxyethylene glycol may be used toform a liquid solution for dispensing and the aforesaid solvents may beused to replace the water and/or the ethanol described above. Glycerin,propylene glycol and polyoxyethylene glycol may be the sole solvent orused as mixtures of the same or mixed with water, alcohol or theirmixtures. Flavoring materials may be added when desired.

In place of the sodium bisulfite described above, there may besubstituted in equimolar proportions a compound selected from the groupconsisting of sodium sulfite, sodium metabisulfite, sodium dithionate,sodium hydrosulfite, sodium hyposulfite, lithium sulfite, lithiumbisulfite, lighium metabisulfite, lithium dithionate, lithiumhydrosulfite, lithium hyposulfite, potassium sulfite, potassiumbisulfite, potassium metabisulfite, potassium dithionate, potassiumhydrosulfite and potassium hyposulfite.

EXAMPLE 10

To a freshly prepared solution containing 50 grams of choline salicylateper 100 ml. is added 1.25 grams of choline salicylate sodiummetabisulfite. The mixture is stirred, filtered and packaged in unitdosage form for dispensing. The new pharmaceutical composition will besubstantially free of color even on prolonged storage. The solvent toprepare said solution may be water, ethanol, glycerin, propylene glycol,polyoxyethylene glycol or mixtures of the same. Appropriate flavors maybe added if desired.

In place of the choline salicylate sodium metabisulfite described above,there may be substituted in equal weight a compound selected from thegroup consisting of choline salicylate sodium sulfite, cholinesalicylate sodium bisulfite, choline salicylate sodium dithionate,choline salicylate sodium hydrosulfite, choline salicylate hyposulfite,choline salicylate potassium sulfite, choline salicylate potassiumbisulfite, choline salicylate potassium metabisulfite, cholinesalicylate potassium dithionate, choline salicylate potassiumhydrosulfite, choline salicylate potassium hyposulfite, cholinesalicylate lithium sulfite, choline salicylate lithium bisulfite,choline salicylate lithium metabilsulfite, choline salicylate lithiumdithionate, choline salicylate lithium hydrosulfite, choline salicylatelithium hyposulfite, in similar concentration to that described forcholine salicylate sodium metabisulfite. The optimal effective range forcolor stabilization for the said choline salicylate alkali metalsulfitecontaining compounds described above is not less than 0.01percent by weight and not more than 5.0 percent by weight and preferably0.5 percent to 2.5 percent by weight based on the weight of activesalicylate compound used.

EXAMPLE 11

When a solid dosage form is desired, as for example, capsules, tablets,ointments or gels, then either a concentrated solution of cholinesalicylate, as for example, containing from 80 percent to 90 percent byweight of choline salicylate, or the solid form of choline salicylate isused. The stabilizing new compound, as for example, choline salicylatelithium metabisulfite, 0.05 percent by weight, is added to the cholinesalicylate prior to its incorporation into the base or vehicle. Theremainder of the steps required to prepare the respective pharmaceuticalpreparation is well known to the art and remains the same and theresulting product will be found to be free of color formation even onprolonged storage.

When preparing a tablet, such carriers and/or diluents as magnesiumsulfate, lactose, sucrose, starch or mixtures of the same may be usedwith either a concentrated solution of choline salicylate or its dryform. After the incorporation of the active ingredients and thestabilizing compound with the diluent and/or carrier, suitablegranulating agents and tablet lubricants may be added. Tablets ofsuitable size containing the appropriate quantity of choline salicylateare then prepared by compression.

When capsules are preferred, a mixture of the above described carrierplus the active ingredient and the appropriate quantity of thecolorstabilizing new compound described herein, are filled directly intocapsules of appropriate size and shape.

When ointments, gels and suppositories are desired, then the activeingredients and selected color-stabilizing new compound are mixed andadded to the appropriate pharmaceutically acceptable ointment base, gelvehicle or suppository base and the whole milled to achieve a uniformdistribution. The finished ointment or gel preparation is then packagedin unit dosage form for dispensing while the suppository mass is shapedinto suppositories of suitable size for dispensing.

EXAMPLE 12

In place of the choline salicylate used to form the choline salicylatesulfite-containing compound, there may be substituted in equimolarquantities, N-methylglucamine salicylate, aspirin, para-amino salicylateand its metal salts, salicylic acid and its metal salts, and esters ofsalicylic acid, to form corresponding salicylate sulfite-containingcompounds. Said corresponding salicylate alkali metal sulfite-containingcompound, prepared in the manner set forth above, possesses the sameproperty of suppressing color formation in pharmaceutical compositionsas does choline salicylate sulfitecontaining compounds. The formedcorresponding salicylate sulfite-containing compounds have the fullpharmaco-therapeutic properties of the respective salicylate moieties,such as analgesia, antipyretic and local anti-inflammatory actions,while the para-amino salicylate alkali metal sulfite-containingcompounds have in addition, an anti-tubercular action. The above newcompounds may be used in therapy as liquid or solid pharmaceuticalpreparations administered either orally, topically or rectally.

EXAMPLE 13

When it is desired to suppress the color in a salicylate-containingpharmaceutical preparation then not less than 0.1 percent by weight andnot more than 5.0 percent by weight of the appropriate cholinesalicylate sulfite-containing compound is incorporated into thesalicylate-containing pharmaceutical preparation intended to bestabilized against color formation. Pharmaceutical preparationscontaining such salicylate compounds as aspirin, salicylic acid,metallic salts of salicylic acid, para-aminosalicylic acid, metallicsalts of para-aminosalicylic acid, esters of salicylic acid such asmethyl salicylate and menthyl salicylate and N-methylglucaminesalicylate may be rendered free of color formation through the use ofthe aforesaid new compounds. The particular salicylate-containingpharmaceutical dosage form to be stabilized may be either a solid dosageform as for example, tablets, powders, lozenges, suppositories,ointments, creams, gels or a liquid dosage form as for example,solutions, tinctures, elixirs and syrups.

In achieving color stabilization of a salicylate-containingpharmaceutical preparation, as for example, a gel, then 8.72 grams ofN-methyl-glucammonium salicylate are mixed with 0.05 grams of cholinesalicylate sodium metabisulfite and the whole dissolved in 40 cc. ofethyl alcohol. When solution is complete, cetyldimethylbenzylammoniumchloride, 0.01 gram, is added to the ethanol and the whole filtered.Suitable flavoring agents may be added, if desired, to the alcoholsolution.

In a separate flask containing 40 ml. of distilled water is dispersed2.75 grams of methyl cellulose-4000 and 5 grams of glycerin. Thesolution is heated to approximately 50° C and mixed with the aforesaidalcohol solution. The mixture is filtered and the pH adjusted so that itis between pH 5 and pH 7. The mixture is rapidly chilled to form a gell,which is then packaged in unit containers. The resultant gel will befree of color formation, even after storage for prolonged periods oftime.

When it is desired to stabilize an emulsion containing a salicylatecompound, as for example, menthyl salicylate, then 0.25 gram of cholinesalicylate sodium bisulfite is dissolved in 50 ml. of peanut oil and tothis is added 1 gram of menthyl salicylate. Warming may be used tofacilitate solution. In a separate vessel containing 50 ml. of distilledwater is added 2 grams of sorbitolmono-oleate and the aqueous solutionadded to the peanut oil and the whole homogenized. The resultantpreparation is a white emulsion useful as a sun-screen dermatologicpreparation that will not form a color even on prolonged storage.

To an 0.5 gram of choline salicylate potassium sulfite is added 100grams of para-aminosalicylic acid and the mixture tumbled until auniform dispersion results. The resultant bulk powder may be stored forprolonged periods of time without a change in color and may be used infurther pharmaceutical manufacture.

What is claimed is:
 1. A choline salicylate sulfite-containing compoundselected from the group consisting of choline salicylate sodiumbisulfite, choline salicylate sodium metabisulfite, choline salicylatesodium dithionate, choline salicylate sodium hydrosulfite, cholinesalicylate sodium hyposulfite, choline salicylate potassium bisulfite,choline salicylate potassium metabisulfite, choline salicylate potassiumdithionate, choline salicylate potassium hydrosulfite, cholinesalicylate potassium hyposulfite, choline salicylate lithium bisulfite,choline salicylate lithium metabisulfite, choline salicylate lithiumdithionate, choline salicylate lithium hydrosulfite and cholinesalicylate lithium hyposulfite.
 2. The compound of claim 1 said compoundbeing choline salicylate sodium bisulfite.
 3. The compound of claim 1said compound being choline salicylate sodium metabisulfite.
 4. Thecompound of claim 1 said compound being choline salicylate sodiumdithionate.
 5. The compound of claim 1 said compound being cholinesalicylate sodium hydrosulfite.
 6. The compound of claim 1 said compoundbeing choline salicylate sodium hyposulfite.
 7. The compound of claim 1said compound being choline salicylate potassium bisulfite.
 8. Thecompound of claim 1 said compound being choline salicylate potassiummetabisulfite.
 9. The compound of claim 1 said compound being cholinesalicylate potassium dithionate.
 10. The compound of claim 1 saidcompound being choline salicylate potassium hydrosulfite.
 11. Thecompound of claim 1 said compound being choline salicylate potassiumhyposulfite.
 12. The compound of claim 1 said compound being cholinesalicylate lithium bisulfite.
 13. The compound of claim 1 said compoundbeing choline salicylate lithium metabisulfite.
 14. The compound ofclaim 1 said compound being choline salicylate lithium dithionate. 15.The compound of claim 1 said compound being choline salicylate lithiumhydrosulfite.
 16. The compound of claim 1 said compound being cholinesalicylate lithium hyposulfite.